Abstract (Description) Alcohol intake stimulates release of free fatty acids (FFAs) from white adipose tissue and increases uptake of FFAs into hepatocytes, thereby promoting liver steatosis and alcoholic liver disease (ALD). Blocking trafficking of FFAs to the liver likely holds a promise for preventing/treating ALD; however, tissues and cell types that control FFA trafficking and distributions remain elusive. Recent studies highlight the metabolic function of brown adipose tissue (BAT) and beige fat in humans and rodents. BAT and beige fat defend body temperature homeostasis through thermogenesis, and protect against obesity through increasing energy expenditure. UCP1 is expressed exclusively in BAT and beige fat and mediates heat production and energy expenditure. Deletion of UCP1 impairs BAT/beige fat function. In humans, deficiency in UCP1-expressing brown/beige adipocytes increases risk for obesity and metabolic diseases. Surprisingly, the role of BAT and beige fat in ALD progression has not been examined, given that they primarily burn FFAs to fuel UCP1-mediated thermogenesis. We speculated that BAT and beige fat defend liver homeostasis against steatosis by suppressing hepatic influx of FFAs. In the preliminary data, we found that inactivation of BAT and beige fat, through genetic deletion of UCP1, markedly exacerbates alcohol-induced liver steatosis, injury, inflammation, and fibrosis. Remarkably, alcohol intake substantially increases UCP1 expression in BAT. Alcohol also stimulates expression of alcohol metabolic enzyme Cyp2E1 in both mouse BAT and brown adipocyte cultures, suggesting that BAT has intrinsic alcohol-sensing capability. Moreover, blocking sympathetic inputs to BAT impairs the ability of alcohol to stimulate UCP1 expression, indicating that a brain-sympathetic nerve axis mediates alcohol stimulation of BAT and beige fat. Based on these novel findings, we hypothesize that alcohol intake stimulates BAT and beige fat both directly through their intrinsic alcohol-sensing machinery and indirectly via the brain-sympathetic nerve pathways. BAT and beige fat burn FFAs, thereby suppressing trafficking of FFAs into the liver and protecting against ALD. Additionally, BAT and beige fat also secrete hepatoprotective endocrine factors that defend liver against injury, inflammation, and fibrosis. This project will interrogate the underlying mechanisms mediating crosstalk between BAT/beige fat and liver in the context of ALD. Aim 1: Delineate how alcohol consumption activates BAT and beige fat. We will test the hypothesis that alcohol stimulates BAT/beige fat both directly and indirectly. We will characterize the components of the direct and indirect pathways. Aim 2: Delineate how BAT and beige fat protect against ALD. We will test the hypothesis that BAT and beige fat protect against ALD by burning FFAs and secreting hepatoprotective endocrine factors. The outcomes of this project are expected to define BAT/beige fat as unrecognized alcohol senior and as a novel defender against ALD, thereby opening a new BAT/beige fat area in the ALD field.